Effects of gel volume on pharmacokinetics for vaginal and rectal applications of combination DuoGel-IQB4012, a dual chamber-dual drug HIV microbicide gel, in pigtailed macaques

Abstract

This study evaluated effects of differing gel volumes on pharmacokinetics (PK). IQB4012, a gel containing the non-nucleoside reverse transcriptase inhibitor IQP-0528 and tenofovir (TFV), was applied to the pigtailed macaque vagina and rectum. Vaginal gel volumes (1% loading of both drugs) were 0.5 or 1.5 ml; following wash-out, 1 or 4 ml of gel were then applied rectally. Blood, vaginal, and rectal fluids were collected at 0, 2, 4, and 24 h. Vaginal and rectal tissue biopsies were collected at 4 and 24 h. There were no statistically significant differences in concentrations for either drug between gel volumes within compartments at matched time points. After vaginal gel application, median IQP-0528 concentrations were ~ 10-10 ng/g, 10-10 ng/ml, and 10-10 ng/ml in vaginal tissues, vaginal fluids, and rectal fluids, respectively (over 24 h). Median vaginal TFV concentrations were 1-2 logs lower than IQP-0528 levels at matched time points. After rectal gel application, median IQP-0528 and TFV concentrations in rectal fluids were ~ 10-10 ng/ml and ~ 10-10 ng/ml, respectively. Concentrations of both drugs sampled in rectal tissues were low (~ 10-10 ng/g). For 1 ml gel, half of sampled rectal tissues had undetectable concentrations of either drug, and over half of sampled rectal fluids had undetectable TFV concentrations. These results indicate differences in drug delivery between the vaginal and rectal compartments, and that smaller vaginal gel volumes may not significantly compromise microbicide PK and prophylactic potential. However, effects of rectal gel volume on PK for both drugs were less definitive.

Smart Freeze-Dried Bigels for the Prevention of the Sexual Transmission of HIV by Accelerating the Vaginal Release of Tenofovir during Intercourse

“…Some of these polymers have been used to obtain mucoadhesive vaginal dosage forms for the controlled release of anti-HIV drugs. Among them it is worth highlighting chitosan—alone [20] or in combination with pectin [21]—cellulose derivatives [22], and Carbopol ® [23].…”

Deducing Mucosal Pharmacokinetics and Pharmacodynamics of the Anti-HIV Molecule Tenofovir from Measurements in Blood

“…We do note that even for the advanced modeling, the approach here requires an effective longitudinal average of luminal and mucosal drug concentrations, for comparison with the volume-averaged values in blood. There has been experimental analysis of longitudinal dependence of microbicide delivery along the vaginal canal in non-human primates 55 . Statistically significant differences along the canal were not found, but the high variability in experimental PK data compromised the incisiveness of those comparisons.…”